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1.  High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals 
Bioconjugate chemistry  2015;27(1):179-188.
Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched 72Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure 72As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming 72Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation.
doi:10.1021/acs.bioconjchem.5b00592
PMCID: PMC4720530  PMID: 26646989
2.  A Porphyrin-PEG Polymer with Rapid Renal Clearance 
Biomaterials  2015;76:25-32.
Tetracarboxylic porphyrins and polyethylene glycol (PEG) diamines were crosslinked in conditions that gave rise to a water-soluble porphyrin polyamide. Using PEG linkers 2 kDa or larger prevented fluorescence self-quenching. This networked porphyrin mesh was retained during dialysis with membranes with a 100 kDa pore size, yet passed through the membrane when centrifugal filtration was applied. Following intravenous administration, the porphyrin mesh, but not the free porphyrin, was rapidly cleared via renal excretion. The process could be monitored by fluorescence analysis of collected urine, with minimal background due to the large Stokes shift of the porphyrin (230 nm separating excitation and emission peaks). In a rhabdomyolysis mouse model of renal failure, porphyrin mesh urinary clearance was significantly impaired. This led to slower accumulation in the bladder, which could be visualized non-invasively via fluorescence imaging. Without further modification, the porphyrin mesh was chelated with 64Cu for dynamic whole body positron emission tomography imaging of renal clearance. Together, these data show that small porphyrin-PEG polymers can serve as effective multimodal markers of renal function.
doi:10.1016/j.biomaterials.2015.10.049
PMCID: PMC4662896  PMID: 26517562
Porphyrin; Polyamide; fluorescence imaging; positron emission tomography; renal clearance; acute renal failure
3.  LGR4 Is a Direct Target of MicroRNA-34a and Modulates the Proliferation and Migration of Retinal Pigment Epithelial ARPE-19 Cells 
PLoS ONE  2016;11(12):e0168320.
The pathology of proliferative vitreoretinopathy and proliferative diabetic retinopathy is linked to proliferation, migration, and adhesion of the retinal pigment epithelium. MicroRNA-34a (miR-34a) expression modulates changes in proliferation and migration of retinal pigment epithelial cell line ARPE-19. In this study, we determined that miR-34a interacts with LGR4, identified by bioinformatics using TargetScan Human 5.0, to affect these changes. Double luciferase gene reporter assay confirmed miR-34a involvement in mediating control. miR-34a mimic transfection decreased LGR4 expression. Western blot analysis documented corresponding protein expression inhibition. MTS, Ki67 immunostaining, scratch and transwell testing, along with attachment assay showed that miR-34a upregulation inhibited ARPE-19 cell proliferation, migration and attachment partly through downregulation of LGR4 protein expression. Western blot analysis revealed that both miR-34a upregulation and LGR4 downregulation induced declines in E2F1, p-CDC2, CDK2, CDK4 and CDK6 protein expression. Taken together, miR-34a gene expression upregulation inhibits ARPE-19 cell proliferation, migration and adhesion partly by suppressing LGR4 expression. These results substantiate earlier indications that both miR-34a and LGR4 are potential drug targets to prevent fibrosis in a clinical setting.
doi:10.1371/journal.pone.0168320
PMCID: PMC5158047  PMID: 27977785
4.  Probiotics enhance the effect of allergy immunotherapy on regulating antigen specific B cell activity in asthma patients 
Immune regulatory system dysfunction plays a role in the pathogenesis of asthma. The therapeutic effect of allergic asthma is to be improved. The immune regulatory function of probiotics has been recognized. This study tests a hypothesis that Clostridium butyricum (CB) enhances the effect of allergen specific immunotherapy (AIT) on asthma. In this study patients with allergic asthma were treated with AIT or/and CB for six months. The therapeutic effect and IgE production of the patients were observed. The results showed that administration with AIT alone alleviated the asthma symptoms; but the serum levels of interleukin (IL)-4, IL-5, IL-13 and specific IgE were not altered, which was markedly improved by the administration with CB plus AIT. Such effects were maintained only for two months in the patients treated with AIT alone; but maintained more than 12 months in those patients treated with both AIT and CB. CB facilitated AIT to induce IL-10+ B cells (B10 cells) in asthma patients. AIT/CB therapy converted antigen specific B cells to antigen specific regulatory B cells. Butyrate modulated the gene transcription of IgE and IL-10 in the allergen specific B cells. In conclusion, administration of CB can enhance the therapeutic effect of AIT in the treatment of allergic asthma via facilitating generation of B10 cells.
PMCID: PMC5209480  PMID: 28078000
Allergy; asthma; allergen specific immunotherapy; IgE; probiotics
5.  Intrinsically 89Zr-labeled Gd2O2S:Eu nanophosphors with high in vivo stability for dual-modality imaging 
Radioluminescence imaging (RLI) employs high energy particles from radioisotope decay for in situ excitation of selected nanophosphors. Co-injection of radiopharmaceuticals and nanophosphors suffers from suboptimal RL efficiency owing to the large separation between the source and the emitter. In addition, vastly different pharmacokinetic profiles of the two further impede the practical applications of this approach. To overcome the above challenges, chelator-free radiolabeled nanophosphors with excellent RL efficiency and dual-modality imaging capabilities have been proposed. Abundant O2- donors on Gd2O2S:Eu could intrinsically chelate oxophilic radionuclide 89Zr with ~80 % labeling yield. Positron emission tomography demonstrated superb long-term radiostability of [89Zr]Gd2O2S:Eu@PEG nanoparticles in vivo, and a conventional optical imaging system was used to study radiouminescence properties of [89Zr]Gd2O2S:Eu@PEG nanoparticles in vitro and in vivo.
PMCID: PMC5209509  PMID: 28078029
Radioluminescence; gadolinium oxysulfide; positron emission tomography; multimodality imaging; nanophosphors
6.  Role and mechanism of the AMPK pathway in waterborne Zn exposure influencing the hepatic energy metabolism of Synechogobius hasta 
Scientific Reports  2016;6:38716.
Previous studies have investigated the physiological responses in the liver of Synechogobius hasta exposed to waterborne zinc (Zn). However, at present, very little is known about the underlying molecular mechanisms of these responses. In this study, RNA sequencing (RNA-seq) was performed to analyse the differences in the hepatic transcriptomes between control and Zn-exposed S. hasta. A total of 36,339 unigenes and 1,615 bp of unigene N50 were detected. These genes were further annotated to the Nonredundant protein (NR), Nonredundant nucleotide (Nt), Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG), Clusters of Orthologous Groups (COG) and Gene Ontology (GO) databases. After 60 days of Zn exposure, 708 and 237 genes were significantly up- and down-regulated, respectively. Many differentially expressed genes (DEGs) involved in energy metabolic pathways were identified, and their expression profiles suggested increased catabolic processes and reduced biosynthetic processes. These changes indicated that waterborne Zn exposure increased the energy production and requirement, which was related to the activation of the AMPK signalling pathway. Furthermore, using the primary hepatocytes of S. hasta, we identified the role of the AMPK signalling pathway in Zn-influenced energy metabolism.
doi:10.1038/srep38716
PMCID: PMC5146659  PMID: 27934965
7.  Nox5 Stability and Superoxide Production is Regulated by C-terminal Binding of Hsp90 and Co-Chaperones 
Heat shock protein 90 (Hsp90) is a molecular chaperone that orchestrates the folding and stability of proteins that regulate cellular signaling, proliferation and inflammation. We have previously shown that Hsp90 controls the production of reactive oxygen species by modulating the activity of Noxes1-3 and 5, but not Nox4. The goal of the current study was to define the regions on Nox5 that bind Hsp90 and determine how Hsp90 regulates enzyme activity. In isolated enzyme activity assays, we found that Hsp90 inhibitors selectively decrease superoxide, but not hydrogen peroxide, production. The addition of Hsp90 alone only modestly increases Nox5 enzyme activity but in combination with the co-chaperones, Hsp70, HOP, Hsp40, and p23 it robustly stimulated superoxide, but not hydrogen peroxide, production. Proximity ligation assays reveal that Nox5 and Hsp90 interact in intact cells. In cell lysates using a co-IP approach, Hsp90 binds to Nox5 but not Nox4, and the degree of binding can be influenced by calcium-dependent stimuli. Inhibition of Hsp90 induced the degradation of full length, catalytically inactive and a C-terminal fragment (aa398–719) of Nox5. In contrast, inhibition of Hsp90 did not affect the expression levels of N-terminal fragments (aa1–550) suggesting that Hsp90 binding maintains the stability of C-terminal regions. In Co-IP assays, Hsp90 was bound only to the C-terminal region of Nox5. Further refinement using deletion analysis revealed that the region between aa490–550 mediates Hsp90 binding. Converse mapping experiments show that the C-terminal region of Nox5 bound to the M domain of Hsp90 (aa310–529). In addition to Hsp90, Nox5 bound other components of the foldosome including co-chaperones Hsp70, HOP, p23 and Hsp40. Silencing of HOP, Hsp40 and p23 reduced Nox5-dependent superoxide. In contrast, increased expression of Hsp70 decreased Nox5 activity whereas a mutant of Hsp70 failed to do so. Inhibition of Hsp90 results in the loss of higher molecular weight complexes of Nox5 and decreased interaction between monomers. Collectively these results show that the C-terminal region of Nox5 binds to the M domain of Hsp90 and that the binding of Hsp90 and select co-chaperones facilitate oligomerization and the efficient production of superoxide.
doi:10.1016/j.freeradbiomed.2015.09.019
PMCID: PMC4751585  PMID: 26456056
NADPH oxidase; Nox; Hsp90; Hsp70; co-chaperones; vascular biology
8.  Main Effects of Diagnoses, Brain Regions, and their Interaction Effects for Cerebral Metabolites in Bipolar and Unipolar Depressive Disorders 
Scientific Reports  2016;6:37343.
Previous studies suggested patients with bipolar depressive disorder (BDd) or unipolar depressive disorder (UDd) have cerebral metabolites abnormalities. These abnormalities may stem from multiple sub-regions of gray matter in brain regions. Thirteen BDd patients, 20 UDd patients and 20 healthy controls (HC) were enrolled to investigate these abnormalities. Absolute concentrations of 5 cerebral metabolites (glutamate-glutamine (Glx), N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), parietal cortex (PC)) were measured from 4 subregions (the medial frontal cortex (mPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parietal cortex (PC)) of gray matter. Main and interaction effects of cerebral metabolites across subregions of gray matter were evaluated. For example, the Glx was significantly higher in BDd compared with UDd, and so on. As the interaction analyses showed, some interaction effects existed. The concentrations of BDds’ Glx, Cho, Cr in the ACC and HCs’ mI and Cr in the PC were higher than that of other interaction effects. In addition, the concentrations of BDds’ Glx and Cr in the PC and HCs’ mI in the ACC were statistically significant lower than that of other interaction effects. These findings point to region-related abnormalities of cerebral metabolites across subjects with BDd and UDd.
doi:10.1038/srep37343
PMCID: PMC5116758  PMID: 27869127
10.  Engineering Intrinsically Zirconium-89 Radiolabeled Self-Destructing Mesoporous Silica Nanostructures for In Vivo Biodistribution and Tumor Targeting Studies 
We present a systematic study of in vitro and in vivo behavior of biodegradable mesoporous silica nanoparticles (bMSNs), designed to carry multiple cargos (both small and macro-molecular drugs) and subsequently self-destruct following release of their payloads. Complete degradation of bMSNs was seen within 21 days of incubation in simulated body fluid. The as-synthesized bMSNs were intrinsically radiolabeled with oxophilic zirconium-89 (89Zr, t1/2=78.4 h) radionuclide to track their in vivo pharmacokinetics via positron emission tomography (PET) imaging. Rapid and persistent CD105 specific tumor vasculature targeting was successfully demonstrated in murine model of metastatic breast cancer by using TRC105 (an anti-CD105 antibody)-conjugated bMSNs. This study serves to illustrate a simple, versatile and readily tunable approach to potentially overcome the current challenges facing nanomedicine and further the goals of personalized nanotheranostics.
Graphical Abstract
Self-destructing, intrinsically zirconium-89 labeled mesoporous silica nanoparticles are reported for angiogenesis-targeted positron emission tomography in metastatic breast tumor models. The simple and versatile approach paves way for future personalized nanotheranostics through simple surface modifications; to label a wide range of clinically relevant radioisotopes bypassing specific chelator chemistries, carry multiple drug cargos for combination therapy and target multiple tumor types.
doi:10.1002/advs.201600122
PMCID: PMC5102673  PMID: 27980987
Biodegradable mesoporous silica nanoparticles; Intrinsic radiolabeling; Positron emission tomography (PET) imaging; Vasculature targeting
11.  Gingival Crevicular Fluid as a Novel Potential Source of Biomarkers Distinguishes Pubertal from Post-Pubertal Subjects 
Diagnostics  2016;6(4):41.
Detection of pubertal growth peak is vital in orthodontic treatment timing and planning. Gingival crevicular fluid (GCF) contains abundant proteins from different sources and has been proven to be an ideal source of biomarkers. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) is an advanced technique that can detect low-molecular-weight peptides with high sensitivity and resolution. The aim of this research was to identify novel candidate biomarkers in GCF to help the diagnosis of pubertal growth peak by MALDI-TOF/MS. Results showed that the peak intensities of six peptides were significantly different between two groups: 1660.2 Da, 1783.0 Da, 2912.5 Da, 4178.6 Da, 5064.9 Da, and 6108.9 Da and are considered to be potential candidate biomarkers to identify pubertal growth peak. Further studies are needed to identify sequence information of these candidate biomarkers.
doi:10.3390/diagnostics6040041
PMCID: PMC5192516  PMID: 27869666
gingival crevicular fluid (GCF); matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS); pubertal growth peak
12.  Salvianolic acid B reduced the formation of epidural fibrosis in an experimental rat model 
Background
Salvianolic acid B (Sal B) was newly reported to be able to attenuate fibrosis in the animal model. The aim of the present study was to investigate the effect of the intragastric application of Sal B on the prevention of epidural fibrosis (EF).
Methods
Forty healthy adult male Wistar rats were divided into four treatment groups (n = 10 per group): (1) 10 mg/kg Sal B, (2) 30 mg/kg Sal B, (3) 50 mg/kg Sal B and (4) Saline (vehicle treatment, control group). All animals underwent a laminectomy at the lumbar 1–2 (L 1–2) level. After intragastric treatment, all rats were sacrificed at post-operative week 8. The extent of the epidural scar, the regeneration of the vasculature and the expression levels of vascular endothelial growth factor (VEGF) were analysed.
Results
The animals’ recovery was uneventful during the experimental period. The extent of the epidural scar, the regeneration of the vasculature and the expression levels of VEGF suggested better outcomes in the Sal B-treated groups. Sal B exerted the ability to prevent the formation of an epidural scar and vascularization at the laminectomy sites. The effects of Sal B were dose-dependent, with the 50 mg/kg Sal B group showing the best outcomes compared with the other groups.
Conclusions
Post-operative intragastric application of Sal B can prevent the formation of epidural scarring. Sal B exerted these effects in a dose-dependent manner, and 50 mg/kg dose was shown to be the best effect in the present study. The results of this study reveal that Sal B could be a potential therapy for EF and valuable for further research.
doi:10.1186/s13018-016-0475-x
PMCID: PMC5112727  PMID: 27852325
Animal experimentation; Laminectomy; Salvia
13.  Electrically Tunable Nd:YAG waveguide laser based on Graphene 
Scientific Reports  2016;6:36785.
We demonstrate a tunable hybrid Graphene-Nd:YAG cladding waveguide laser exploiting the electro-optic and the Joule heating effects of Graphene. A cladding Nd:YAG waveguide was fabricated by the ion irradiation. The multi-layer graphene were transferred onto the waveguide surface as the saturable absorber to get the Q-switched pulsed laser oscillation in the waveguide. Composing with appropriate electrodes, graphene based capacitance and heater were formed on the surface of the Nd:YAG waveguide. Through electrical control of graphene, the state of the hybrid waveguide laser was turned on or off. And the laser operation of the hybrid waveguide was electrically tuned between the continuous wave laser and the nanosecond pulsed laser.
doi:10.1038/srep36785
PMCID: PMC5105065  PMID: 27833114
14.  Engineering Intrinsically Zirconium‐89 Radiolabeled Self‐Destructing Mesoporous Silica Nanostructures for In Vivo Biodistribution and Tumor Targeting Studies 
Advanced Science  2016;3(11):1600122.
A systematic study of in vitro and in vivo behavior of biodegradable mesoporous silica nanoparticles (bMSNs), designed to carry multiple cargos (both small and macromolecular drugs) and subsequently self‐destruct following release of their payloads, is presented. Complete degradation of bMSNs is seen within 21 d of incubation in simulated body fluid. The as‐synthesized bMSNs are intrinsically radiolabeled with oxophilic zirconium‐89 (89Zr, t 1/2 = 78.4 h) radionuclide to track their in vivo pharmacokinetics via positron emission tomography imaging. Rapid and persistent CD105 specific tumor vasculature targeting is successfully demonstrated in murine model of metastatic breast cancer by using TRC105 (an anti‐CD105 antibody)‐conjugated bMSNs. This study serves to illustrate a simple, versatile, and readily tunable approach to potentially overcome the current challenges facing nanomedicine and further the goals of personalized nanotheranostics.
doi:10.1002/advs.201600122
PMCID: PMC5102673  PMID: 27980987
biodegradable mesoporous silica nanoparticles; intrinsic radiolabeling; positron emission tomography (PET) imaging; vasculature targeting
15.  The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis 
Nature Communications  2016;7:13436.
Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. miR-24 reduces the levels of Smad4 required for the expression of IRAK-M and also downregulates key lipid-processing molecule SR-B1. IRAK-M deficiency in turn leads to elevated miR-24 levels, sustains disruption of monocyte homeostasis and aggravates atherosclerosis. Our data define an integrated feedback circuit in monocytes and its disruption may lead to non-resolving low-grade inflammation conducive to atherosclerosis.
Chronic low-grade inflammation has been suspected to promote atherosclerosis. Here, Geng et al. show that sustained low-grade inflammation promotes atherosclerosis in mice via monocyte programing that involves a coupled disruption of IRAK-M regulation and induction of miR-24.
doi:10.1038/ncomms13436
PMCID: PMC5105176  PMID: 27824038
16.  Transgenic soybean overexpressing GmSAMT1 exhibits resistance to multiple‐HG types of soybean cyst nematode Heterodera glycines  
Plant Biotechnology Journal  2016;14(11):2100-2109.
Summary
Soybean (Glycine max (L.) Merr.) salicylic acid methyl transferase (GmSAMT1) catalyses the conversion of salicylic acid to methyl salicylate. Prior results showed that when GmSAMT1 was overexpressed in transgenic soybean hairy roots, resistance is conferred against soybean cyst nematode (SCN), Heterodera glycines Ichinohe. In this study, we produced transgenic soybean overexpressing GmSAMT1 and characterized their response to various SCN races. Transgenic plants conferred a significant reduction in the development of SCN HG type 1.2.5.7 (race 2), HG type 0 (race 3) and HG type 2.5.7 (race 5). Among transgenic lines, GmSAMT1 expression in roots was positively associated with SCN resistance. In some transgenic lines, there was a significant decrease in salicylic acid titer relative to control plants. No significant seed yield differences were observed between transgenics and control soybean plants grown in one greenhouse with 22 °C day/night temperature, whereas transgenic soybean had higher yield than controls grown a warmer greenhouse (27 °C day/23 °C night) temperature. In a 1‐year field experiment in Knoxville, TN, there was no significant difference in seed yield between the transgenic and nontransgenic soybean under conditions with negligible SCN infection. We hypothesize that GmSAMT1 expression affects salicylic acid biosynthesis, which, in turn, attenuates SCN development, without negative consequences to soybean yield or other morphological traits. Thus, we conclude that GmSAMT1 overexpression confers broad resistance to multiple SCN races, which would be potentially applicable to commercial production.
doi:10.1111/pbi.12566
PMCID: PMC5095773  PMID: 27064027
salicylic acid methyltransferase; transgenic soybean; soybean cyst nematode; gene expression; metabolite; female index; yield
17.  Effect of N-Perfluorooctane on Hypoxia/Reoxygenation Injury in Human Umbilical Vein Endothelial Cells  
Acta Cardiologica Sinica  2016;32(6):716-722.
Background
This study investigated the effect of n-perfluorooctane (PFC) on hypoxia/reoxygenation (H/R) injury in human umbilical vein endothelial cells (HUVECs).
Methods
In this study, the H/R models were prepared by chemical methods (using dithionite solution). The experimental groups included the control group, the PFC group with a culture volume ratio of 10%, the H/R model group, and treatment groups with various doses of PFC + H/R (i.e., 5%, 10%, or 20% PFC by volume). The cell counting kit-8 (CCK-8) method was used to assay cell viability. Colorimetric assays were used to estimate the leakage of lactate dehydrogenase (LDH) in the medium, the levels of intracellular malondialdehyde (MDA) and nitric oxide (NO), and the activity of superoxide dismutase (SOD). Western blot was used to analyze the expression of the apoptosis-related protein cystine aspartate proteolytic enzyme 3 (caspase-3).
Results
Compared with the control group, every detected index of 10% PFC group had no statistical significance (p > 0.05). Compared with the model group, 10% and 20% PFC treatment groups could increase cell viability A, decrease the content of NO and reduce caspase-3 expression (p < 0.05); Every PFC treatment group could significantly reduce the release of LDH and the contents of MDA, and also increase the activities of SOD (p < 0.01).
Conclusions
PFC has a significant protective effect on HUVEC H/R injury, which may be related to the inhibition of oxidative stress and inflammation and further enhance cell antioxidant and anti-apoptotic characteristics.
PMCID: PMC5126450  PMID: 27899859
Apoptosis; Endothelial cells; Hypoxia/reoxygenation; N-perfluorooctane; Oxidative stress
18.  Crash Frequency Analysis Using Hurdle Models with Random Effects Considering Short-Term Panel Data 
Random effect panel data hurdle models are established to research the daily crash frequency on a mountainous section of highway I-70 in Colorado. Road Weather Information System (RWIS) real-time traffic and weather and road surface conditions are merged into the models incorporating road characteristics. The random effect hurdle negative binomial (REHNB) model is developed to study the daily crash frequency along with three other competing models. The proposed model considers the serial correlation of observations, the unbalanced panel-data structure, and dominating zeroes. Based on several statistical tests, the REHNB model is identified as the most appropriate one among four candidate models for a typical mountainous highway. The results show that: (1) the presence of over-dispersion in the short-term crash frequency data is due to both excess zeros and unobserved heterogeneity in the crash data; and (2) the REHNB model is suitable for this type of data. Moreover, time-varying variables including weather conditions, road surface conditions and traffic conditions are found to play importation roles in crash frequency. Besides the methodological advancements, the proposed technology bears great potential for engineering applications to develop short-term crash frequency models by utilizing detailed data from field monitoring data such as RWIS, which is becoming more accessible around the world.
doi:10.3390/ijerph13111043
PMCID: PMC5129253  PMID: 27792209
daily crash frequency; short-term driving environment; panel data; hurdle negative binomial; random effect
19.  IMG/VR: a database of cultured and uncultured DNA Viruses and retroviruses 
Nucleic Acids Research  2016;45(Database issue):D457-D465.
Viruses represent the most abundant life forms on the planet. Recent experimental and computational improvements have led to a dramatic increase in the number of viral genome sequences identified primarily from metagenomic samples. As a result of the expanding catalog of metagenomic viral sequences, there exists a need for a comprehensive computational platform integrating all these sequences with associated metadata and analytical tools. Here we present IMG/VR (https://img.jgi.doe.gov/vr/), the largest publicly available database of 3908 isolate reference DNA viruses with 264 413 computationally identified viral contigs from >6000 ecologically diverse metagenomic samples. Approximately half of the viral contigs are grouped into genetically distinct quasi-species clusters. Microbial hosts are predicted for 20 000 viral sequences, revealing nine microbial phyla previously unreported to be infected by viruses. Viral sequences can be queried using a variety of associated metadata, including habitat type and geographic location of the samples, or taxonomic classification according to hallmark viral genes. IMG/VR has a user-friendly interface that allows users to interrogate all integrated data and interact by comparing with external sequences, thus serving as an essential resource in the viral genomics community.
doi:10.1093/nar/gkw1030
PMCID: PMC5210529  PMID: 27799466
20.  Reprogramming macrophage orientation by microRNA 146b targeting transcription factor IRF5 
EBioMedicine  2016;14:83-96.
The regulation of macrophage orientation pathological conditions is important but still incompletely understood. Here, we show that IL-10 and Rag1 double knockout mice spontaneously develop colitis with dominant M1 macrophage phenotype, suggesting that IL-10 regulates macrophage orientation in inflammation. We demonstrate that IL-10 stimulation induced miR-146b expression, and that the expression of miR-146b was impaired in IL-10 deficient macrophages. Our data show that miR-146b targets IRF5, resulting in the regulation of macrophage activation. Furthermore, miR-146b deficient mice developed intestinal inflammation with enhanced M1 macrophage polarization. Finally, miR-146b mimic treatment significantly suppresses M1 macrophage activation and ameliorates colitis development in vivo. Collectively, the results suggest that IL-10 dependent miR-146b plays an important role in the modulation of M1 macrophage orientation.
Highlights
•Interleukin 10-induced miR-146b plays a critical role in the regulation of macrophage polarization and colitis development by targeting IRF5.•Treatment with miR-146b mimic significantly suppresses M1 macrophage activation and ameliorates colitis development.
Interleukin 10 and Interleukin receptor are clearly involved in the development of inflammatory bowel diseases and other inflammatory diseases. Notably, the mutation of Interleukin 10 and Interleukin 10 receptor are clearly correlated with inflammatory bowel diseases. In the present study we show that Interleukin 10-induced miR-146b plays a critical role in the regulation of macrophage polarization and colitis development by targeting IRF5. Treatment with miR-146b mimic significantly suppresses M1 macrophage activation and ameliorates colitis development. The results highlight the potent role of miR146b in the control of immune responses and pathogenesis of inflammatory diseases.
doi:10.1016/j.ebiom.2016.10.041
PMCID: PMC5161420  PMID: 27825654
Interleukin 10; miR-146b; Macrophage; CRISPR/Cas9; Colitis
21.  Discrimination of transgenic soybean seeds by terahertz spectroscopy 
Scientific Reports  2016;6:35799.
Discrimination of genetically modified organisms is increasingly demanded by legislation and consumers worldwide. The feasibility of a non-destructive discrimination of glyphosate-resistant and conventional soybean seeds and their hybrid descendants was examined by terahertz time-domain spectroscopy system combined with chemometrics. Principal component analysis (PCA), least squares-support vector machines (LS-SVM) and PCA-back propagation neural network (PCA-BPNN) models with the first and second derivative and standard normal variate (SNV) transformation pre-treatments were applied to classify soybean seeds based on genotype. Results demonstrated clear differences among glyphosate-resistant, hybrid descendants and conventional non-transformed soybean seeds could easily be visualized with an excellent classification (accuracy was 88.33% in validation set) using the LS-SVM and the spectra with SNV pre-treatment. The results indicated that THz spectroscopy techniques together with chemometrics would be a promising technique to distinguish transgenic soybean seeds from non-transformed seeds with high efficiency and without any major sample preparation.
doi:10.1038/srep35799
PMCID: PMC5080623  PMID: 27782205
22.  Motion-corrected Fourier ptychography 
Biomedical Optics Express  2016;7(11):4543-4553.
Fourier ptychography (FP) is a recently proposed computational imaging technique for high space-bandwidth product imaging. In real setups such as endoscope and transmission electron microscope, the common sample motion largely degrades the FP reconstruction and limits its practicability. In this paper, we propose a novel FP reconstruction method to efficiently correct for unknown sample motion. Specifically, we adaptively update the sample’s Fourier spectrum from low spatial-frequency regions towards high spatial-frequency ones, with an additional motion recovery and phase-offset compensation procedure for each sub-spectrum. Benefiting from the phase retrieval redundancy theory, the required large overlap between adjacent sub-spectra offers an accurate guide for successful motion recovery. Experimental results on both simulated data and real captured data show that the proposed method can correct for unknown sample motion with its standard deviation being up to 10% of the field-of-view scale. We have released our source code for non-commercial use, and it may find wide applications in related FP platforms such as endoscopy and transmission electron microscopy.
doi:10.1364/BOE.7.004543
PMCID: PMC5119594  PMID: 27895994
(170.3010) Image reconstruction techniques; (110.1758) Computational imaging; (170.0180) Microscopy
23.  Biodegradable and Renal Clearable Inorganic Nanoparticles 
Advanced Science  2015;3(2):1500223.
Personalized treatment plans for cancer therapy have been at the forefront of oncology research for many years. With the advent of many novel nanoplatforms, this goal is closer to realization today than ever before. Inorganic nanoparticles hold immense potential in the field of nano‐oncology, but have considerable toxicity concerns that have limited their translation to date. In this review, an overview of emerging biologically safe inorganic nanoplatforms is provided, along with considerations of the challenges that need to be overcome for cancer theranostics with inorganic nanoparticles to become a reality. The clinical and preclinical studies of both biodegradable and renal clearable inorganic nanoparticles are discussed, along with their implications.
doi:10.1002/advs.201500223
PMCID: PMC4944857  PMID: 27429897
biodegradable; inorganic nanoparticles; molecular imaging; renal clearance; theranostics
24.  Electrospinning of calcium phosphate-poly (d,l-lactic acid) nanofibers for sustained release of water-soluble drug and fast mineralization 
Calcium phosphate-based biomaterials have been well studied in biomedical fields due to their outstanding chemical and biological properties which are similar to the inorganic constituents in bone tissue. In this study, amorphous calcium phosphate (ACP) nanoparticles were prepared by a precipitation method, and used for preparation of ACP-poly(d,l-lactic acid) (ACP-PLA) nanofibers and water-soluble drug-containing ACP-PLA nanofibers by electrospinning. Promoting the encapsulation efficiency of water-soluble drugs in electrospun hydrophobic polymer nanofibers is a common problem due to the incompatibility between the water-soluble drug molecules and hydrophobic polymers solution. Herein, we used a native biomolecule of lecithin as a biocompatible surfactant to overcome this problem, and successfully prepared water-soluble drug-containing ACP-PLA nanofibers. The lecithin and ACP nanoparticles played important roles in stabilizing water-soluble drug in the electrospinning composite solution. The electrospun drug-containing ACP-PLA nanofibers exhibited fast mineralization in simulated body fluid. The ACP nanoparticles played the key role of seeds in the process of mineralization. Furthermore, the drug-containing ACP-PLA nanofibers exhibited sustained drug release which simultaneously occurred with the in situ mineralization in simulated body fluid. The osteoblast-like (MG63) cells with spreading filopodia were well observed on the as-prepared nanofibrous mats after culturing for 24 hours, indicating a high cytocompatibility. Due to the high biocompatibility, sustained drug release, and fast mineralization, the as-prepared composite nanofibers may have potential applications in water-soluble drug loading and release for tissue engineering.
doi:10.2147/IJN.S114224
PMCID: PMC5063602  PMID: 27785016
calcium phosphate; water-soluble drug; nanofibers; drug release; electrospinning
25.  Diversity and Variation of Bacterial Community Revealed by MiSeq Sequencing in Chinese Dark Teas 
PLoS ONE  2016;11(9):e0162719.
Chinese dark teas (CDTs) are now among the popular tea beverages worldwide due to their unique health benefits. Because the production of CDTs involves fermentation that is characterized by the effect of microbes, microorganisms are believed to play critical roles in the determination of the chemical characteristics of CDTs. Some dominant fungi have been identified from CDTs. In contrast, little, if anything, is known about the composition of bacterial community in CDTs. This study was set to investigate the diversity and variation of bacterial community in four major types of CDTs from China. First, the composition of the bacterial community of CDTs was determined using MiSeq sequencing. From the four typical CDTs, a total of 238 genera that belong to 128 families of bacteria were detected, including most of the families of beneficial bacteria known to be associated with fermented food. While different types of CDTs had generally distinct bacterial structures, the two types of brick teas produced from adjacent regions displayed strong similarity in bacterial composition, suggesting that the producing environment and processing condition perhaps together influence bacterial succession in CDTs. The global characterization of bacterial communities in CDTs is an essential first step for us to understand their function in fermentation and their potential impact on human health. Such knowledge will be important guidance for improving the production of CDTs with higher quality and elevated health benefits.
doi:10.1371/journal.pone.0162719
PMCID: PMC5045175  PMID: 27690376

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